ABSTRACT Older adults who are socially isolated have increased risk of all-cause mortality, and several specific infectious, neoplastic, and cardiovascular diseases. However, the neurobiologic and genomic mechanisms of these effects remain largely unexplored. Our preliminary studies have found that subjective social isolation is associated with sleep disturbance as well as increases in markers of inflammation. The over-arching objective of this study is to evaluate subjective social isolation in older adults and the consequences of such social isolation for the homeostatic regulation of sleep and inflammatory biology dynamics. Given our findings that cellular and genomic activation of inflammatory markers occurs along with subjective social isolation as well as sleep disturbance, this study will test the consequences of naturalistic and experimental sleep loss on feelings of social connection and cellular and genomic markers of inflammation in socially isolated vs. socially integrated older adults. The study aims are: 1) to determine the nature and severity of disordered sleep in socially isolated older adults; 2) to evaluate cellular and genomic markers of inflammation in socially isolated older adults; and 3) to examine the contribution of sleep loss and recovery sleep to behavioral symptoms and cellular and genomic markers of inflammation in socially isolated older adults. Understanding the consequences of social isolation for the homeostatic regulation of sleep within the framework of an observational and experimental research design has implications for identifying the psychobiological pathways that might drive the link between social isolation and health. Given that sleep loss induces elevations in proinflammatory cytokine activity, dysregulation of the bi-directional relationship between sleep and cytokines may result in a feed-forward loop in which disrupted sleep and elevated proinflammatory cytokines create a vicious cycle exacerbating sleep and contributing to feelings of social disconnection. Results of this study have immediate clinical implications for the development of interventions that target disordered sleep with potential effects on morbidity and outcomes in subjectively socially isolated older adults.